Development of an In silico Model for Screening Potential ALOX15 Inhibitors Toward Ferroptosis Modulation

Abstract

Ferroptosis is a distinct form of regulated cell death that is closely associated with several major diseases. Therefore, modulating ferroptosis has emerged as a promising therapeutic strategy, with ALOX15 highlighted as a key target. This study developed a multi-layered in silico framework to rapidly identify potential ALOX15 inhibitors through three stages. First, known ALOX15 inhibitors were collected and curated from the ChEMBL database. Next, two screening models, pharmacophore modeling and molecular docking, were constructed and evaluated to characterize essential chemical features involved in binding to ALOX15. Finally, the integrated model was applied to three large natural-product libraries (COCONUT, Phenol Explorer and NPASS), combining ADMET filtering, pharmacophore matching, and docking to prioritize promising candidates. From tens of thousands of compounds, 30 molecules with the highest docking scores underwent advanced ADMET evaluation. Five compounds emerged as top candidates, showing a strong balance of predicted bioactivity, multi-organ safety, and pre-clinical development potential. These molecules represent promising roles in developing ferroptosis-modulating therapeutics through ALOX15 inhibition. The study recommends expanding the model to additional compound libraries and performing in vitro and in vivo experiments to validate biological activity.